Research · PIM kinases · Bench to clinic
PIM1 inhibition: from a mouse model to a Phase 1/2 trial.
TP-3654, now Nuvisertib.
PIM1 expression is markedly elevated in MPN progenitors. Genetic ablation blocks myelofibrosis; the small-molecule PIM1 inhibitor TP-3654 ameliorates disease in mice. The work led directly to a multicenter clinical trial, with UVA Cancer Center as a major site.
Most preclinical drug candidates die between the mouse and the patient. The lab's PIM1 work is one of the rare cases where a hypothesis tested in a knockout mouse moved through industry partnership into a multicenter trial — and recently into FDA Fast Track and EMA Orphan Drug designations. The compound now has a name (Nuvisertib) and patients on it.
PIM1 is a serine/threonine kinase that sits downstream of cytokine signaling and supports proliferation, survival, and metabolic adaptation in hematopoietic cells. The lab found PIM1 expression markedly elevated in MPN progenitors and asked whether it's a passenger of the disease state or a driver of it.
Genetic Pim1 ablation in JAK2V617F mice answered the question: the mutant clone proliferates less, splenomegaly recedes, and bone marrow fibrosis fails to develop. The PIM1 axis is causal, not correlative.
Pharmacologically, the small-molecule PIM1 inhibitor TP-3654 reproduces the genetic phenotype in mice — reducing leukocytosis, splenomegaly, and fibrotic markers, with concurrent inhibition of mTORC1, MYC, and TGF-β signaling and lower collagen output. Combination with Ruxolitinib delivers more than additive benefit: blood counts normalize and marrow fibrosis is abrogated, suggesting non-overlapping mechanisms.
The compound is now Nuvisertib, in a Sumitomo Pharma-sponsored Phase 1/2 trial (NCT04176198) at UVA Cancer Center and other sites. As of mid-2025 it carries FDA Fast Track, EMA Orphan Drug, and Japan MHLW Orphan Drug designations. CDK6, independently elevated in MPN progenitors, is a parallel target: Palbociclib + Ruxolitinib synergize in mouse models, suggesting a portfolio of combination strategies.
What the lab has shown directly, with anchors to the published papers.
- 01
PIM1 expression elevated in MPN progenitors; genetic ablation prevents myelofibrosis.
- 02
TP-3654 reduces leukocytosis, splenomegaly, and bone marrow fibrosis in murine MPN.
- 03
TP-3654 inhibits mTORC1, MYC, and TGF-β signaling and reduces collagen output.
- 04
Combined TP-3654 + Ruxolitinib normalizes blood counts and abrogates marrow fibrosis.
- 05
CDK6 is independently elevated in MPN progenitors; Palbociclib + Ruxolitinib synergize.
Which patients benefit most — by mutation status, by treatment history, by marrow fibrosis grade? Will combination strategies (PIM + JAK, PIM + CDK4/6) translate? The lab is positioned to answer mechanistic questions that the trial alone cannot.
01
PMID 34741118 ↗2022Leukemia36(3):746-759
Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models
Dutta A, Nath D, Yang Y, Le BT, Rahman MF, Faughnan P, Wang Z, Stuver M, He R, Tan W, Hutchison RE, Foulks JM, Warner SL, Zang C, Mohi G
02
PMID 34145036 ↗2021Cancer Research81(16):4332-4345
CDK6 Is a Therapeutic Target in Myelofibrosis
Dutta A, Nath D, Yang Y, Le BT, Mohi G
The full archive
The complete bibliography lives on the publications page.
Lab page on UVA BMG: Research themes ↗ · Contact: gm7sj@virginia.edu